Selective activation of antioxidant resources and energy deficiency in Marinesco–Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss
Abstract Marinesco–Sjögren syndrome (MSS) is a neuromuscular disease which presents with ataxia, muscle weakness and cataracts. This syndrome is typically caused by mutations in SIL1 gene, an ER co-chaperone that disrupts protein folding. Although it is known that accumulation of misfolded proteins...
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Nature Portfolio
2025-04-01
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| Online Access: | https://doi.org/10.1038/s41598-025-96467-9 |
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| author | Valeria Panella Francesca Potenza Carla Tatone Lorenza Speranza Fernanda Amicarelli Michele Sallese |
| author_facet | Valeria Panella Francesca Potenza Carla Tatone Lorenza Speranza Fernanda Amicarelli Michele Sallese |
| author_sort | Valeria Panella |
| collection | DOAJ |
| description | Abstract Marinesco–Sjögren syndrome (MSS) is a neuromuscular disease which presents with ataxia, muscle weakness and cataracts. This syndrome is typically caused by mutations in SIL1 gene, an ER co-chaperone that disrupts protein folding. Although it is known that accumulation of misfolded proteins in the ER profoundly affect reduction–oxidation (redox) homeostasis and energy production, the possible role of these processes in MSS was not investigated to date. In patient-derived fibroblasts, both maximal mitochondrial respiration and mitochondrial ATP production rates were diminished, while the glycolytic fraction remained unaffected. Catalase and superoxide dismutase activities were increased, while glutathione peroxidase and glutathione reductase were decreased. Oxidative damage to lipids, proteins, and DNA was comparable or even lower to that observed in control cells. Similar alterations were observed in the muscle tissue of the woozy mouse model of MSS. In conclusion, we identified a mitochondrial energy deficit and an adaptive cellular mechanism that effectively manage oxidative stress in Sil1-deficient cells. |
| format | Article |
| id | doaj-art-72098e5dba564882a083b82abef5f2b0 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-72098e5dba564882a083b82abef5f2b02025-08-20T03:10:10ZengNature PortfolioScientific Reports2045-23222025-04-0115111310.1038/s41598-025-96467-9Selective activation of antioxidant resources and energy deficiency in Marinesco–Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 lossValeria Panella0Francesca Potenza1Carla Tatone2Lorenza Speranza3Fernanda Amicarelli4Michele Sallese5Department of Medicine and Aging Sciences, “G. d’ Annunzio” University of Chieti-PescaraDepartment of Innovative Technologies in Medicine and Dentistry, “G. d’ Annunzio” University of Chieti-PescaraDepartment of Life, Health and Environmental Sciences, University of L’AquilaDepartment of Medicine and Aging Sciences, “G. d’ Annunzio” University of Chieti-PescaraDepartment of Life, Health and Environmental Sciences, University of L’AquilaDepartment of Innovative Technologies in Medicine and Dentistry, “G. d’ Annunzio” University of Chieti-PescaraAbstract Marinesco–Sjögren syndrome (MSS) is a neuromuscular disease which presents with ataxia, muscle weakness and cataracts. This syndrome is typically caused by mutations in SIL1 gene, an ER co-chaperone that disrupts protein folding. Although it is known that accumulation of misfolded proteins in the ER profoundly affect reduction–oxidation (redox) homeostasis and energy production, the possible role of these processes in MSS was not investigated to date. In patient-derived fibroblasts, both maximal mitochondrial respiration and mitochondrial ATP production rates were diminished, while the glycolytic fraction remained unaffected. Catalase and superoxide dismutase activities were increased, while glutathione peroxidase and glutathione reductase were decreased. Oxidative damage to lipids, proteins, and DNA was comparable or even lower to that observed in control cells. Similar alterations were observed in the muscle tissue of the woozy mouse model of MSS. In conclusion, we identified a mitochondrial energy deficit and an adaptive cellular mechanism that effectively manage oxidative stress in Sil1-deficient cells.https://doi.org/10.1038/s41598-025-96467-9Neurodegenerative diseaseAtaxiaMitochondriaEnergy deficiencyCatalaseSuperoxide dismutase |
| spellingShingle | Valeria Panella Francesca Potenza Carla Tatone Lorenza Speranza Fernanda Amicarelli Michele Sallese Selective activation of antioxidant resources and energy deficiency in Marinesco–Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss Scientific Reports Neurodegenerative disease Ataxia Mitochondria Energy deficiency Catalase Superoxide dismutase |
| title | Selective activation of antioxidant resources and energy deficiency in Marinesco–Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss |
| title_full | Selective activation of antioxidant resources and energy deficiency in Marinesco–Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss |
| title_fullStr | Selective activation of antioxidant resources and energy deficiency in Marinesco–Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss |
| title_full_unstemmed | Selective activation of antioxidant resources and energy deficiency in Marinesco–Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss |
| title_short | Selective activation of antioxidant resources and energy deficiency in Marinesco–Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss |
| title_sort | selective activation of antioxidant resources and energy deficiency in marinesco sjogren syndrome fibroblasts as an adaptive biological response to sil1 loss |
| topic | Neurodegenerative disease Ataxia Mitochondria Energy deficiency Catalase Superoxide dismutase |
| url | https://doi.org/10.1038/s41598-025-96467-9 |
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